Antiretroviral therapy (ART) has saved millions of lives, but is associated with numerous drawbacks including side-effects, drug resistance, and affordability. Thus, a high priority for the HIV field is the search for strategies to eliminate or control cellular HIV reservoirs, leading to long-term ART-free HIV remission. However, a number of challenges currently hinder our ability to design and test such novel therapies. Two of the most important problems are that: 1) It is unclear what the optimal surrogate endpoint should be for early-phase interventional HIV reservoir trials given our incomplete understanding of the relationship between HIV reservoir measures and the kinetics of viral rebound after treatment interruption; and 2) While there are individuals who can delay/control viremia after ART interruption, we have not yet identified the mechanisms underlying their post-treatment HIV control. Through the proposed studies, we plan to determine the combination of key viral reservoir measurements that best predict HIV rebound and provide an in-depth understanding of the virologic and immunologic mechanisms behind a remarkable cohort of post-treatment controllers. The results may accelerate the evaluation of novel HIV therapeutics and identify new targets for the next generation of HIV therapeutics focused on long-term drug-free HIV remission.